Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribut...Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribute to the progression of ALS,including neuronal oxidative stress and mitochondrial dysfunction.Honokiol(HNK)has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke,Alzheimer’s disease and Parkinson’s disease.Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo.Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins(SOD1-G93A cells for short).Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione(GSH)synthesis and activating the nuclear factor erythroid 2-related factor 2(NRF2)-antioxidant response element(ARE)pathway.Also,honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells.Importantly,honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function.The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice.Overall,honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.展开更多
Bibenzyls,a kind of important plant polyphenols,have attracted growing attention for their broad and remarkable pharmacological activities.However,due to the low abundance in nature,uncontrollable and environmentally ...Bibenzyls,a kind of important plant polyphenols,have attracted growing attention for their broad and remarkable pharmacological activities.However,due to the low abundance in nature,uncontrollable and environmentally unfriendly chemical synthesis processes,these compounds are not readily accessible.Herein,one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes.Three types of efficiently postmodifying modular strains were engineered by employing methyltransferases,prenyltransferase,and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules.Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes.Especially,a prenylated bibenzyl derivative(12)was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke.RNA-seq,quantitative RT-PCR,and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor,mitochondria associated 3(Aifm3),suggesting that Aifm3 might be a new target in ischemic stroke therapy.This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.展开更多
基金supported by the grants from National Natural Science Foundation of China(Nos.82073835 and 81872855)National Key R&D Program of China(No.2019YFC1708901)+2 种基金CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1028)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150,China)Disciplines construction project(201920200802,China)。
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribute to the progression of ALS,including neuronal oxidative stress and mitochondrial dysfunction.Honokiol(HNK)has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke,Alzheimer’s disease and Parkinson’s disease.Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo.Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins(SOD1-G93A cells for short).Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione(GSH)synthesis and activating the nuclear factor erythroid 2-related factor 2(NRF2)-antioxidant response element(ARE)pathway.Also,honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells.Importantly,honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function.The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice.Overall,honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.
基金supported by the National Key Research and Development Program of China(2020YFA0908000)CAMS Innovation fund for Medical Sciences(CIFMS-2021-I2M1-028 and CIFMS-2021-I2M-1-029,China)Beijing Key Laboratory of non-Clinical Drug Metabolism and PK/PD Study(Z141102004414062,China)。
文摘Bibenzyls,a kind of important plant polyphenols,have attracted growing attention for their broad and remarkable pharmacological activities.However,due to the low abundance in nature,uncontrollable and environmentally unfriendly chemical synthesis processes,these compounds are not readily accessible.Herein,one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes.Three types of efficiently postmodifying modular strains were engineered by employing methyltransferases,prenyltransferase,and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules.Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes.Especially,a prenylated bibenzyl derivative(12)was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke.RNA-seq,quantitative RT-PCR,and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor,mitochondria associated 3(Aifm3),suggesting that Aifm3 might be a new target in ischemic stroke therapy.This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.
